Polymers have become an integral component of our society. Advances in synthetic polymer chemistry have allowed plastics to be produced more economically and processed more efficiently than most naturally occurring materials. These advances have enabled the annual production of plastics to increase at a faster rate than lumber, steel, or aluminum in the United States over the last half century. [Mulder, K. F. Technology Forecasting and Social Change 1998, 58, 105.]
Synthetic polymers have also found broad applicability in biological settings. [Kolonko, E. M.; Kiessling, L. L. J. Am. Chem. Soc. 2008, 130, 5626.] Because polymer architectures can be highly modular, changes in polymer template, molecular mass, and function can be tailored to elicit a specific biological recognition or signaling event. A valuable for creating these defined materials is the ring-opening metathesis polymerization (ROMP). [Ivin, K. J. and Mol, J. C. Olefin Metathesis and Metathesis Polymerization. Academic Press: New York, 1997; Grubbs, G. H (ed.) In Handbook of Metathesis; Wiley: VCH; Vol. 3.] Well-defined metal carbene catalysts have been devised that afford control over the polymer chain length and architecture. [L. R. Gilliom, R. H. Grubbs J. Am. Chem. Soc. 1986, 108, 733; K. C. Wallace, R. R. Schrock Macromolecules 1987, 20, 448; R. R. Schrock, S. A. Krouse, K. Knoll, J. Feldman, J. S. Murdzek, D. C. Yang J. Mol. Catal. 1988, 46, 243.] In addition, ruthenium carbene intiators have been developed with excellent air stability and functional group tolerance. [S. T. Nguyen, L. K. Johnson, R. H. Grubbs, J. W. Ziller J. Am. Chem. Soc. 1992, 114, 3974;] J. A. Love, J. P. Morgan, T. M. Trnka, R. H. Grubbs Angew. Chem. Int. Ed. 2002, 41, 4035.] These catalysts enable the synthesis of polymers with a range of functionality. [S. Hilf, A. F. M. Kilbinger Nat. Chem. 2009, 1, 537; K. H. Mortell, R. V. Weatherman, L. L. Kiessling J. Am. Chem. Soc. 1996, 118, 2297; L. L. Kiessling, J. E. Gestwicki, L. E. Strong Curr. Opin. Chem. Biol. 2000, 4, 696; E. B. Puffer, J. K. Pontrello, J. J. Hollenbeck, J. A. Kink, L. L. Kiessling A.C.S. Chem. Biol. 2007, 2, 252; M. J. Borrok, E. M. Kolonko, L. L. Kiessling A.C.S. Chem. Biol. 2008, 3, 101; A. H. Courtney, E. B. Puffer, J. K. Pontrello, Z.-Q. Yang, L. L. Kiessling Proc. Natl. Acad. Sci. 2009, 106, 2500; K. A. Baessler, Y. Lee, N. S. Sampson A.C.S. Chem. Biol. 2009, 4, 357; S.-G. Lee, J. M. Brown, C. J. Rogers, J. B. Matson, C. Krishnamurthy, M. Rawat, L. C. Hsieh-Wilson Chem. Sci. 2010, 1, 322] ROMP methods have provided access to polymers for diverse applications. [D. Smith, E. B. Pentzer, S. T. Nguyen Polym. Rev. 2007, 47, 419; K. Lienkamp, A. E. Madkour, A. Musante, C. F. Nelson, K. Nusslein, G. N. Tew J. Am. Chem. Soc. 2008, 130, 9836; A. V. Ambade, S. K. Yang, M. Weck Angew. Chem., Int. Ed. 2009, 48, 2894; N. J. Robertson, H. A. I. V. Kostalik, T. J. Clark, P. F. Mutolo, H. D. Abruna, G. W. Coates J. Am. Chem. Soc. 2010, 132, 3400.] In particular applications, bioactive ligands have been appended off the ROMP polymer main chain or chain end. [Kolonko and Kiessling, 2008; Hilf, S, and Kilbinger, A. F. M. Nature Chemistry 2009, 1, 537.] Functional group tolerance has been exploited to design polymers that can interrogate receptor-mediated cellular processes. [a) Kiessling, L. L.; Gestwicki, J. E.; Strong, L. E. Curr. Opin. Chem. Biol. 2000, 4, 696; b) Gestwicki, J. E.; Strong, L. E.; Kiessling, L. L. Chem. Biol. 2000, 7(8), 58; c) Borrok, J. M.; Kolonko, E. M.; Kiessling, L. L. A.C.S. Chem. Bio. 2008, 3(2), 101.]
Extant polymers from ROMP, like the majority of synthetic polymers, are non-degradable. A functional and degradable polymer from ROMP would allow the synthetically useful traits of ROMP reactions to be combined with the growing need for new degradable polymer scaffolds. Because they are non-degradble, the utility of ROMP polymers in many biomedical applications is limited by the cellular toxicities of the non-degradable polymer backbones. [Kolonko and Kiessling, 2008; Kolybaba, M.; Tabil, L. G.; Panigrahi, S.; Crerar, W. J.; Powell, T.; Wang, B. Presented at the 2003 CSAE/ASAE Annual Intersectional Meeting, Fargo, N. Dak., October 2003; paper RRV03-0007; Fournier, E.; Passirani, C.; Montero-Menei, C. N.; Benoit, J. P. Biomaterial 2003. 24, 3311.] A functional and degradable ROMP polymer could allow these biomaterials to be used in vivo by mitigating the side effects caused by prolonged exposure to the hydrolytically stable backbone.
To date, efforts to prepare biodegradable ROMP polymers have afforded polymers that are either functionalizable or partially hydrolysable, but not both (FIG. 1A). For example, polymers wherein a pH- or light-sensitive cleavable linker connects small molecules to the polymer backbone can be used for the controlled release of cargo. [a) Smith, D.; Pentzer, E. B.; Nguyen, S. T. Polymer Rev. 2007, 47, 419; b) Pichavant, L.; Bourget, C.; Durrieu, M.-C.; Héroguez, V. Macromolecules 2011, 44, 7879; c) Johnson, J. A.; Lu, Y. Y.; Burts, A. O.; Lim, Y. H.; Finn, M. G.; Koberstein, J. T.; Turro, N. J.; Tirrell, D. A.; Grubbs, R. H J. Amer. Chem. S. 2011, 133, 559.] Still, the polymeric backbone persists.
Alternatively, partially degradable polymers have been generated. A block copolymer can be generated from a modifiable monomer and a sacrificial dioxepine or dithiepine monomer. [S. Hilf, A. F. M. Kilbinger Nat. Chem. 2009, 1, 537; C. Fraser, M. A. Hillmyer, E. Gutierrez, R. H. Grubbs Macromolecules 1995, 28, 7256; S. Hilf, A. F. M. Kilbinger Macromolecules 2009, 42, 4127.] In this scenario, one block is composed of a non-hydrolysable backbone and the degradable block contains acid-labile acetals or thioacetals that can be cleaved by hydrogenation. Polymers of this type only undergo partial degradation, as one block persists, as shown in FIG. 1A. The current state-of-the-art therefore demands a compromise between generating polymers that can be customized and polymers that can be easily degraded.
U.S. Pat. Nos. 6,271,315 and 6,538,072 relate to functionalization of ROMP monomers and polymers. Each of these patents is incorporated by reference herein for its teachings with respect to functionalization, including reactive functional groups. U.S. Pat. No. 6,291,616 relates to methods for varying the end-groups of ROMP polymers. This patent is incorporated by reference herein in its entirety for a description of such methods which can be applied to the ROMP polymers of this invention.
Alternatively, partially degradable polymers have been generated. A block copolymer can be created from a functionalizable ROMP monomer and a dioxepine or dithiepine monomer. [Hilf, S, and Kilbinger, A. F. M. Nature Chemistry 2009, 1, 537. Hilf, S, and Kilbinger, A. F. M. Macromolecules 2009, 42, 4127.] The cargo-bearing block has a non-hydrolysable backbone, and the degradable block contains acid-labile acetals or thioacetals along the backbone. Following hydrolysis, the non-degradable block is retained as an oligomer. While advances have been made in the art, there remains a significant need for biodegradable ROMP polymers which can be functionalized.
Applying ROMP to synthesize a modifiable homopolymer with a degradable backbone requires a monomer with three important attributes. First, it must be a strained cyclic or bicyclic olefin, so that it undergoes polymerization. [Walker, R.; Conrad, R. M.; Grubbs, R. N. Macromolecules 2009, 42, 599.] Second, it must contain core functionality that gives rise to a polymer that can be degraded. Third, a means to append desired functionality onto the monomer or polymer is needed to enable polymer diversification. Monomers with all of these attributes have been elusive. Many strained olefinic heterocycles spontaneously aromatize. [Boger, D. L.; Mullican, M. D. J. Org. Synth. 1987, 65, 98; K. Afarinkia, V. Vinader, T. D. Nelson, G. H. Posner Tetrahedron 1992, 48, 9111] In addition, attempts to incorporate handles for diversification can further increase monomer instability. [Bandlish, B. K.; Brown, J. N.; Timberlake, J. W.; Trefonas, L. M. J. Org. Chem. 1973, 1973, 1102.] Thus, traditional monomers used in ROMP cannot be simply modified to instill polymer degradability.
Recently, Jeffrey and coworkers reported a novel aza-[4+3] cycloaddition to afford bicyclic compound 3a from furan and hydroxamic ester 2a (Scheme 1A). [Jeffrey, C. S.; Barnes, K. L.; Eickhoff, J. A.; Carson, C. R. J. Amer. Chem. Soc. 2011, 133, 7688.] Calculations of the ring strain of similar frameworks suggest 3a has a ring strain comparable to trans-cyclooctene, which has favorable kinetics of polymerization using ROMP. [Walker et al., 2009; Howell, J.; Goddard, J. D.; Tam, W. Tetrahedron 2009, 65(23), 4562.] Successful ring-opening cross metathesis on architecturally analogous oxybicyclo[3.2.1.]oct-6-en-3-ones had also been reported. [Wright, D. L.; Usher, L. C.; Estrella-Jimenez, M. Org. Lett. 2001, 3(26), 4275; M. D. Mihovilovic, B. Groetzl, W. Kandioller, R. Snajdrova, A. Muskotal, D. A. Bianchi, P. Stanetty Adv. Synth. Catal. 2006, 348, 463] Furthermore, upon ring-opening, a N-alkoxy-1,3-oxazin-4-one motif would be revealed, a framework that should be both acid and base labile (Scheme 1B). [Cardillio, G.; Hashem, M. A.; Tomasini, C. J. Chem. Soc. Perkin Trans 11990, 1487; Bandini, E.; Martelli, G.; Spunta, G.; Bongini, A.; Panunzio, M. Synlett 1999, 11, 1735.]